For many years, the most successful container system for pharmaceutical products has been the combination of elastomeric members in glass vials or other containers such as syringes, bottles and the like. The glass and rubber combination has been useful for a wide variety of pharmaceutical ingredients, combining both safe storage of the medicine and easy access through the elastomeric member. A needle can easily penetrate the rubber stopper to withdraw the desired amount of liquid in a vial without otherwise interfering with the integrity of the closure. Even when powders are stored in vials, the elastomeric member can be penetrated with a needle to activate the powder by adding liquids such as pure water. The activated medicine remains in a safe, protected environment.
The glass and rubber interface has provided reliable seals and a relatively inert environment for the medicaments. For example, in syringes, the syringe tip may be manufactured from an elastomeric material. Its function is to slide along the interior wall of the syringe while maintaining a seal between the syringe tip and the cartridge. At the same time, the syringe tip made from elastomeric materials should not contaminate the contents of the syringe. Sleeve stoppers, elastomeric caps, flash back bulbs, center seals between two compartment vial packages and other elastomeric members have also been found to be useful in combination with glass and plastic objects not only in the pharmaceutical industry but in other industries.
Because of the success of these types of pharmaceutical devices, and as more and more systems have been using rubber in combination with glass containers, the rate at which these devices can be assembled contributes greatly to the economic efficiencies of this otherwise desirable component design. For example, conventional pharmaceutical assembly machines which are useful for filling vials rely on a mechanical implantation of a rubber stopper into the neck of the vial or other shaped container. Just prior to the mechanical insertion, the rubber stoppers are transported from the hopper to the stoppering equipment, usually by centrifugal, vibrating or gravity feed. It is essential that the rubber components not hang up on each other or on the transfer equipment. It is essential that they flow smoothly into the capping or closure forming device. Plastic containers are also becoming more useful in pharmaceutical containers.
The equipment used for transferring components is typically made from stainless steel or other materials which can be kept extremely clean for pharmaceutical purposes. The ability of the rubber component to move smoothly on the surface is directly dependent upon its coefficient of friction, with lower values for coefficient of friction being far more desirable. Also, it is at least as important that the elastomeric components do not stick to one another during travel through this transfer equipment.
In Romberg et al U.S. Pat. No. 4,808,453, an elastomeric stopper is described which is suitable for use with containers, wherein the co-efficient of friction of the stopper is reduced to less than about 1.0 through the use of a continuous polyparaxylylene coating. Stoppers and other elastomeric materials which are manufactured according to Romberg et al function effectively in mechanical hoppers and stoppering equipment generally. In addition, the pharmaceutical elastomeric coatings described in Romberg et al have been able to protect the contents of the container from contamination by extractable metals in the elastomeric base material. The use of silicone oil as a lubricant to prevent rubber products from sticking or binding to one another is also eliminated. Elimination of the silicone oil greatly reduces a source of particles which, while not particularly harmful or undesirable by themselves, are included in the total particle count. The Food and Drug Administration places a maximum on the number of particles present, without concern for the source of the particles. Thus, silicone oil is to be avoided.
Similarly, elastomeric materials which are used in the pharmaceutical industry have been carefully selected and formulated to be as inert as possible when in contact with pharmaceutical products such as medicines and the like. Formulations and products are checked constantly to determine that they are not being contaminated. Of particular importance, in addition to the above mentioned particle count produced by silicone oil, are particles which are extracted from the elastomeric closure itself. Certain trace metals are employed in the manufacture of elastomeric compounds, such as catalysts and other additives. It is essential that no extraction of these materials take place by the liquids which come in contact with the elastomeric member. Of particular concern are metals such as calcium and aluminum, and heavy metals such as zinc and lead. Accelerated and ultra vigorous testing is used to determine the amount of these undesirable materials which potentially may be extracted from the rubber. If the actual quantity of extractable metals present after vigorous testing is within the "safe" level, then the use of the elastomeric material under normal conditions would likely result in a nearly contamination free product.
Gorham U.S. Pat. No. 3,288,728 discloses a basis method of preparing linear co-polymers from paraxylylenes using temperature conditions between 450.degree. C. and 700.degree. C. This patent suggest that small articles can be protected or encapsulated with these polymers to obtain the insulative and protective properties of the polyparaxylylenes. The patent generally suggests that there are enumerable possible applications for the polymer as a coating material.
Gorham U.S. Pat. No. 3,342,754 describes the broad method of preparing linear polymers of paraxylylene and particularly in preparing coatings using this material. The patent is replete with a variety of examples of variations and suggests that these polymers are desirable for use as a film, fiber, surface coating, or electrical insulation. Both this patent and the previous Gorham patent offer the general suggestion that almost any material may be coated with paraxylylene polymers, although neither has a specific example relative to the pharmaceutical industry.
U.S. Pat. No. 3,379,803 describes apparatus and methods useful for polymerizing paraxylylene and applying this material as a continuous film on a wide variety of substrates. U.S. Pat. No. 4,225,647 discloses a process for coating an extremely broad list of materials with polymers of paraxylylene. This patent suggests that a first layer of substituted silicon compounds be employed prior to the polyparaxylylene coating.
Gorham et al U.S. Pat. No. 3,300,332 describes a coating process wherein an object is to be coated with an insoluble coating. The thickness is not described in detail, but Gorham suggests that the thickness is not narrowly critical. He describes a coating of 0.1 mil as being very thin and useful when desiring resistance to solvents or reactive attack. In one example, six rubber stoppers are coated to protect them from solvents such as heptane. The amount of coating added ranges from 0.22 to 0.28 grams, which would indicate a thickness of at least 1 mil when standard stoppers are used. Tests have been run which clearly demonstrate that stoppers of the Gorham et al U.S. Pat. No. 3,300,332 are totally non functional as stoppers. In one test, taking the thinnest possible coating, 4 out of 10 stoppers were unable to seal at all. Needle penetration increased by almost a factor of two when compared to an uncoated stopper, again rendering the Gorham et al stoppers unacceptable in the pharmaceutical industry. Of course, Gorham et al does not even suggest that a coating can be used with drugs and the like.
Rubber coatings for pharmaceutical vials are quite old in the art. U.S. Pat. No. 2,649,090 discloses a rubber closure for pharmaceutical vials. U.S. Pat. No. 2,734,649 provides a stopper which is dipped to a desired depth with a coating as an alternative to spraying of the coating on the stopper. U.S. Pat No. 2,747,765; U.S. Pat. No. 4,441,621; and U.S. Pat. No. 4,635,807 all disclose relatively thick coatings on stoppers for various purposes. It has been found in each of these patents the coating itself is incapable of forming a barrier between the stopper and the contents of the vial. In some cases the coating itself is elastomeric and therefore contains those same extractable metals and other impurities which are to avoided.
Finally, U.S. Pat. No. 3,375,110 and U.S. Pat. No. 3,395,016 both disclose the use of polyparaxylylene on the surface of an etchable substrate. Similarly, U.S. Pat. No. 3,375,419 employs etching techniques to place polyparaxylylene film in an area of a transistor device which requires an insulating film. Hofer U.S. Pat. No. 3,895,135 teaches treatment of electrical substrates and suggests that non electrical substrates may also be coated. Hofer describes a constricted flow path along an interface between a masked and unmasked surface with a particular ratio of length to height of about 60 to 1 and preferable 120 to 1. None of these last mentioned patents even address the possibility of applying a polyparaxylylene coating to stoppers and other closures for containers and other devices, particularly in the pharmaceutical industry.
Accordingly, it is an object of this invention to provide a new device for use with pharmaceuticals in which a truly effective seal can be achieved without contamination of the contents.
Another object of this invention is to provide a method for applying a suitable coating to elastomeric closures which provides for an effective seal without contamination.